1. Field of the Invention
The present invention relates to a new use of a chromone derivative as a pharmaceutical composition for the prevention and treatment of fibrosis using epithelial mesenchymal transition (EMT) inhibitory activity and, more particularly, to the novel use of a chromone derivative as an agent for the prevention and treatment of fibrosis, using the activity of the chromone derivative, which has been newly found to inhibit EMT.
2. Description of the Related Art
Fibrosis is a disease in which excess fibrous connective tissue is formed in an organ or tissue in a reparative or developmental process, such fibrous connective tissue being distinguished from normally formed fibrous tissue. When excess fibrous connective tissue is formed in an organ or tissue, the tissue becomes hard and the inflow of body fluids may decrease, making it impossible to sufficiently perform inherent living functions. It is known to be caused by injuries, inflammation, burns, radiation, chemotherapy, lymphedema, etc. Problems related to fibrosis may vary depending on the location at which fibrous connective tissue is formed, and the liver, glands, and lungs are mainly damaged. Typical examples of fibrosis include idiopathic pulmonary fibrosis (IPF), myelofibrosis, liver fibrosis, and kidney fibrosis.
Idiopathic pulmonary fibrosis is an interstitial lung disease, which chronically progresses and has a bad prognosis and for which therapeutic methods have not yet been proven. It is diagnosed when a honeycomb shape or an irregular shape is observed in a lung biopsy. Dyspnea gradually occurs, and hypoxia or myocardial infarction is caused, undesirably leading to death. The causes thereof have not been determined to date, but are considered to be due to various factors, such as the environment, viruses, heredity, toxic compounds, etc., to thus incur inflammation in the lungs, and fibrous cells are excessively manipulated during the recovery of such inflammation, whereby fibrosis progresses in the lungs.
Myelofibrosis is a bone marrow disorder in which excessive fibrous tissue formation occurs, thus disrupting the production of blood cells and changing the numbers of erythrocytes and leukocytes and the action thereof. It includes idiopathic myelofibrosis and secondary myelofibrosis. Specifically, idiopathic myelofibrosis exhibits severe fibroplasias of the systemic bone marrow, hypertrophy symptoms, and immature granulocytes or nucleated erythrocytes in the peripheral blood. The cause thereof is not obvious, but is deemed to be due to poisoning of the bone marrow, inflammation, etc. Secondary myelofibrosis is caused during the progression of leukemia, malignant lymphoma, bone marrow metastasis of cancer, poisoning by chemicals, etc. Effective therapeutic agents therefor have not yet been developed.
Liver fibrosis is also referred to as “liver cirrhosis”, and is a disease in which the function of the liver is deteriorated due to the conversion of normal liver tissue into fibrotic tissue, such as regenerative nodules, because of chronic inflammation. It mainly occurs when the inflammatory state of the liver continues due to chronic hepatitis B or C, excessive alcohol consumption, or hepatotoxic substances. The treatment thereof aims to slow the progression of symptoms as much as possible. Although antiviral drugs may be used depending on the causes thereof, the effects thereof are unknown for different cases.
Kidney fibrosis is a progressive disease in which extracellular matrix accumulates, thus causing fibrosis in the kidneys, and includes glomerular sclerosis and tubular interstitial fibrosis. Side effects occur in the kidneys due to the fibrosis of the kidneys. It is caused by trauma, infection, surgery, environmental factors, chemicals, radiation exposure, etc., and may give rise to symptoms such as pain, urinary issues, nausea, vomiting, etc. Although such symptoms are controlled using drugs or via kidney transplantation, there is a need to develop an effective therapeutic agent therefor.
Meanwhile, Grande et al. recently reported research results in which Twist and Snail, main regulators of epithelial mesenchymal transition (hereinafter, referred to as “EMT”), play an important role in fibrosis of the kidneys, and Lovisa et al. also reported that EMT has a strong effect on kidney fibrosis. EMT refers to the phenomenon by which normal cells undergo genetic reprogramming in the form of mesenchymal cells, which are easily transportable due to changes in the cytoskeleton in intermediate stages during transformation into tumor cells. Hence, metastasis and the proliferation of tumors are considered to be suppressed when the expression of EMT-associated proteins is inhibited, and thus thorough research into EMT is being carried out in order to develop tumor therapeutic agents. Hundreds of EMT regulators, including Twist, Snail, Slug, E-Cadherin, Vimentin, Collagen1 α1, etc., are known.
Suzuki et al. reported that DEC2 (BHLHE41) is a transcriptional repressor of Twist, which is an EMT regulator, and when the expression of DEC2 is suppressed, EMT is activated, thus resulting in malignant tumors. Also, Sato et al. reported that DEC2 functions to inhibit the expression of Slug, which is an EMT regulator, to thus suppress the formation of malignant tumors induced by TGF-β. In addition thereto, many researchers have reported the association of an EMT regulator with cancer metastasis using DEC2.
Research into EMT and EMT regulators has been mainly carried out for cancers or tumors. However, the present inventors have paid attention to the correlation between EMT and fibrosis based on some conventional research results and thus have conceived the notion that if EMT can be regulated, fibrosis can be prevented and treated.
Meanwhile, natural compounds having a chromone (chromen-4-one, 4H-chromen-4-one) structure are typically exemplified by eupatilin, wogonin, myricetin and the like, among which eupatilin is known to be contained in Artemisia asiatica, and has been mainly studied for its anticancer effects.
The present inventors have paid attention to the correlation between EMT and fibrosis and the correlation between DEC2 and EMT and have researched the possibility of using a chromone derivative, including eupatilin, as a therapeutic agent for fibrosis, based on the observation that eupatilin is able to upregulate DEC2 mRNA of macrophages differentiated from bone marrow cells. The inhibitory effect of the chromone derivative on EMT has been newly proven based on cell models and animal models, and fibrosis of the organs or tissues due to the activation of EMT may be effectively inhibited by such compounds, thus culminating in the present invention.